The transdermal delivery of drugs, by diffusion through a body surface, offers improvements over more traditional delivery methods, such as subcutaneous injections and oral delivery. Transdermal drug delivery also avoids the hepatic first pass effect encountered with oral drug delivery. Generally the term “transdermal” when used in reference to drug delivery, broadly encompasses the delivery of an agent through a body surface, such as the skin, mucosa, nails or other body surfaces (e.g., an organ surface) of an animal.
The skin functions as the primary barrier to the transdermal penetration of materials into the body and represents the body's major resistance to the transdermal delivery of beneficial agents such as drugs. To date, efforts have concentrated on reducing the physical resistance of the skin or enhancing the permeability of the skin to facilitate the delivery of drugs by passive diffusion. Various methods of increasing the rate of transdermal drug flux have been attempted, most notably by using chemical flux enhancers.
Other approaches to increase the rates of transdermal drug delivery include the use of alternative energy sources such as electrical energy and ultrasonic energy. Electrically assisted transdermal delivery is also referred to as electrotransport. The term “electrotransport” as used herein refers generally to devices and methods which deliver an agent by electrotransport to the body as well as devices and methods which withdraw or sample body analytes from the body by “reverse” electrotransport. Examples of reverse electrotransport devices for sampling glucose (i.e. for measurement of blood glucose concentration) are disclosed in Guy et al., U.S. Pat. No. 5,362,307 and Glickfeld et al., U.S. Pat. No. 5,279,543. The delivery of a beneficial agent (e.g., a drug) or the withdrawal of a body analyte is generally through a membrane, such as skin, mucous membrane, nails or other body surfaces wherein the delivery or withdrawal is induced or aided by application of an electrical potential. For example, a beneficial agent may be introduced into the systemic circulation of a human body by electrotransport delivery through the skin. A widely used electrotransport process, referred to as electromigration (also called iontophoresis), involves the electrically induced transport of charged ions. Another type of electrotransport, referred to as electroosmosis, involves the flow of a liquid which contains the agent to be delivered, under the influence of an electric field. Still another type of electrotransport process, referred to as electroporation, involves the formation of transiently-existing pores in a biological membrane by the application of a high voltage electric field. An agent can be delivered transdermally either passively (i.e., without electrical assistance) or actively (i.e., under the influence of an electric potential). However, in any given electrotransport process, more than one of these processes, including at least some “passive” diffusion, may be occurring simultaneously to a certain extent. Accordingly, the term “electrotransport”, as used herein, is given its broadest possible interpretation so that it includes the electrically induced or enhanced transport of at least one agent, which may be charged, uncharged, or a mixture thereof, whatever the specific mechanism or mechanisms by which the agent actually is transported.
Electrotransport delivery devices use at least two electrodes that are in electrical contact with some portion of the skin, nails, mucous membrane, or other surface of the body. One electrode, commonly called the “donor” electrode, is the electrode from which the agent is delivered into the body. The other electrode, typically termed the “counter” electrode, serves as a key element in the return circuit which closes the electrical circuit through the body. For example, if the agent to be delivered is positively charged, i.e., a cation, then the anodic electrode is the donor electrode, while the cathodic electrode is the counter electrode which is needed to complete the circuit. Alternatively, if an agent is negatively charged, i.e., an anion, the cathodic electrode is the donor electrode and the anodic electrode is the counter electrode. Additionally, both the anodic and cathodic electrodes may be considered donor electrodes if both anionic and cationic agent ions, or if uncharged dissolved agents, are to be delivered.
Furthermore, electrotransport devices have a donor reservoir, which is a matrix containing the beneficial agent to be delivered, positioned between the donor electrode and the patient's body surface. Preferably, electrotransport devices also have a counter reservoir, containing a physiologically-acceptable salt solution (e.g., buffered saline), positioned between the counter electrode and the patient's body surface. Examples of such reservoirs include a pouch or cavity, a porous sponge or pad, and a hydrophilic polymer or a gel matrix. Such reservoirs are electrically connected to, and positioned between, the anodic or cathodic electrodes and the body surface, to provide a source of one or more agents.
Hydrogels are particularly preferred for use as the drug and electrolyte reservoir matrices, in part, due to the fact that water is the preferred liquid solvent for use in electrotransport drug delivery due to its excellent biocompatability compared with other liquid solvents such as alcohol and glycols. Hydrogels have a high equilibrium water content and can quickly absorb water. In addition, hydrogels tend to have good biocompatibility with the skin and mucosal membranes.
Electrotransport devices also include an electrical power source such as one or more batteries. Typically, at any one time, one pole of the power source is electrically connected to the donor electrode, while the opposite pole is electrically connected to the counter electrode. Since it has been shown that the rate of electrotransport drug delivery is approximately proportional to the amount electric current flowing through the skin and the device, many electrotransport devices typically have an electrical controller that controls the voltage applied through the electrodes, thereby regulating current flow and the rate of drug delivery. These control circuits use a variety of electrical components to control the amplitude, polarity, timing, waveform shape, etc. of the electric current and/or voltage supplied by the power source. See, for example, McNichols et al., U.S. Pat. No. 5,047,007.
Electrotransport delivery devices are often stored not only at the factory but at distribution warehouses and commercial sales locations. As a result, the devices and their components must have extended shelf lives that in some instances must comply with regulatory requirements. For instance, the U.S. Food and Drug Administration has shelf life requirements of from six to eighteen months for some materials. One complicating factor in achieving an extended shelf life is that the aqueous environment in the electrode reservoirs provides an excellent medium for microorganism growth. Accordingly, an antimicrobial agent should be incorporated in the aqueous medium of the electrode reservoirs to inhibit the proliferation of microorganisms.
A number of antimicrobial agents have been used in different environments. Known antimicrobial agents (sometimes referred to as biocides) include chlorinated hydrocarbons, organometallics, halogen-releasing compounds, metallic salts, organic sulfur compounds, quaternary ammonium compounds and phenolics. Illustrative compounds include sorbic acid, benzoic acid, methylparaben and cetylpyridinium chloride. For instance, U.S. Pat. No. 5,434,144 describes topical compositions several of which include methylparaben or a cetylpyridinium salt. Cosmetic Microbiology, A Practical Handbook, D. Brannan, editor teaches on page 167 that alcohols (e.g., ethanol, phenoxyethanol and benzyl alcohol) and glycols (e.g. propylene glycol) can be used as preservative in food, pharmaceutical and drug products. Propylene glycol is said to exhibit a synergistic preservative effect when combined with paraben esters. Cosmetic Microbiology, A Practical Handbook, D. Brannan, editor, p. 167.
In the context of electrotransport devices, propylene glycol has been commonly suggested for use in plasticizing polymeric reservoir matrices. See for example U.S. Pat. No. 4,474,570. Further, propylene glycol has been used in iontophoretic device donor reservoirs to solubilize relatively hydrophobic drugs and other excipients such as stratum corneum lipid modifiers/flux enhancers. See for example U.S. Pat. Nos. 5,527,797 and 5,693,010. Additionally, U.S. Pat. No. 5,668,120 describes at column 8, lines 16-21 that preservatives, such as methylparaben and cetylpyridinium chloride (CPC), can be optionally included in the liquid vehicle of the iontophoresis medium and several of the examples of the patent include such compounds. In addition, U.S. Pat. Nos. 4,585,652 and 5,788,666 disclose that cetylpyridinium chloride can be administered by iontophoresis while U.S. Pat. No. 5,298,017 describes a number of different types of materials which can be administered by electrotransport.